The rules of how amino acids dictate the physical properties of biomolecular condensates are still incomplete. Here, we study condensates formed by tetrapeptides of the form XXssXX. Eight peptides form four types of condensates at different concentrations and pHs: droplets (X = F, L, M, P, V, and A), amorphous dense liquids (X = L, M, P, V, and A), amorphous aggregates (X = W), and gels (X = I, V, and A). The peptides exhibit differences in phase equilibrium and material properties, including a 368-fold range in the threshold concentration for phase separation and a 3,856-fold range in viscosity. All-atom molecular dynamics simulations provide physical explanations of these results. The present work also reveals widespread critical behaviors-including critical slowing down manifested by amorphous dense liquids and critical scaling obeyed by fusion speed-with broad implications for condensate functions.

Tryptophan and its metabolites, produced by the gut microbiota, are pivotal for human physiological and mental health. Yet, quantifying these structurally similar compounds with high specificity remains a challenge, hindering point-of-care diagnostics and targeted therapeutic interventions. Leveraging the innate specificity and adaptability of biological systems, we present a biosensing approach capable of identifying specific metabolites in complex contexts with minimal cross-activity. This study introduces a generalizable strategy that combines evolutionary analysis, key ligand-binding residue identification, and mutagenesis scanning to pinpoint ligand-specific transcription factor variants. Furthermore, we uncover regulatory mechanisms within uncharacterized ligand-binding domains, whether in homodimer interfaces or monomers, through structural prediction and ligand docking. Notably, our "plug-and-play" strategy broadens the detection spectrum, enabling the exclusive biosensing of indole-3-acetic acid (an auxin), tryptamine, indole-3-pyruvic acid, and other tryptophan derivatives in engineered probiotics. This groundwork paves the way to create highly specific transcriptional biosensors for potential clinical, agricultural, and industrial use.

Bioelectronics provide efficient information exchange between living systems and man-made devices, acting as a vital bridge in merging the domains of biology and technology. Using functional fibers as building blocks, bioelectronics could be hierarchically assembled with vast design possibilities across different scales, enhancing their application-specific biointegration, ergonomics, and sustainability. In this work, the authors review recent developments in bioelectronic fiber elements by reflecting on their fabrication approaches and key performance indicators, including the life cycle sustainability, environmental electromechanical performance, and functional adaptabilities. By delving into the challenges associated with physical deployment and exploring innovative design strategies for adaptability, we propose avenues for future development of bioelectronics via fiber building blocks, boosting the potential of "Fiber of Things" for market-ready bioelectronic products with minimized environmental impact.

We explore the potential of clamp-G nucleobase-modified peptide nucleic acids (cGPNAs) as microRNA and messenger RNA inhibitors. For proof of concept, we target miR-155, which is upregulated in diffuse large B cell lymphoma. cGPNA shows significant downregulation of miR-155 and the upregulation of its downstream targets in multiple lymphoma cell lines. Also, cGPNA treatment reduced tumor growth and improved survival in the U2932 cell-derived xenograft mouse model. To assess the broad application of cGPNA as an antisense modality, we also target transthyretin () mRNA. We establish a dose-dependent effect of antisense cGPNA on mRNA levels. For studies, we conjugated cGPNA-based TTR antisense with lactobionic acid-based targeting ligand for liver delivery. We establish that cGPNA exhibits significant TTR protein knockdown compared to unmodified peptide nucleic acid (PNA) . Overall, we confirm that clamp-G-modified PNA analogs are a robust antisense therapy platform.

Amines, hydrazines, and nitrogen-containing heterocycles are pivotal species in medicine, agriculture, fine chemicals, and materials. Diazirines have been recently reported to serve as versatile electrophilic amination reagents for the synthesis of building blocks or late-stage C-N bond formation. Here, we report the catalytic photodecarboxylative amination of carboxylic acids with diazirines under mild conditions. The substrate scope includes broad functional group tolerance, such as ketones, esters, olefins, and alcohols, along with the late-stage amination of naproxen, ibuprofen, gemfibrozil, and gibberellic acid. Synthetic applications leverage the versatility of the intermediate diaziridines and include the regioselective preparation of a suite of 1-indazoles, 2-indazoles, and fluoroquinolones.

Sustainability is critical in addressing global challenges posed by prolonged pandemics that impact health, economies, and the environment. Here, we introduce a molecular engineering approach for thermoregulated antimicrobial management inspired by firewalking rituals. The study uses spectroscopy and multi-scale modeling to validate a hierarchical design. Efficient light-to-thermal energy conversion is achieved by engineering the molecular band structure. Rapid nanoscale hyperthermia is facilitated through thermal engineering. This approach significantly reduces the half-life of pathogens such as , influenza A, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to 1.4 min while maintaining a low perceived temperature on human skin. Standard disease infection and epidemic models show this technology's potential to flatten outbreak curves and delay peak infection rates, which is crucial during the early stages of pandemics when developing vaccines and antiviral drugs takes time. The scalable manufacturing and broad antimicrobial applicability hold great promise for controlling emerging infectious diseases and diverse bioprotective applications.

In colloids, the shape influences the function. In silica, straight nanorods have already been synthesized from water-in-oil emulsions. By contrast, curly silica nanofibers have been less reported because the underlying growth mechanism remains unexplored, hindering further morphology control for applications. Herein, we describe the synthetic protocol for silica nanofibers with a tunable curliness based on the control of the water-in-oil emulsion droplets. Systematically decreasing the droplet size and increasing their contact angle, the Brownian motion of the droplets intensifies during the silica growth, thus increasing the random curliness of the nanofibers. This finding is supported by simplistic theoretical arguments and experimentally verified by varying the temperature to finely tune the curliness. Assembling these nanofibers toward porous disordered films enhances multiple scattering in the visible range, resulting in increased whiteness in contrast to films constructed by spherical and rod-like building units, which can be useful for, e.g., coatings and pigments.

Interstitial fluid (ISF) contains a wealth of biomolecules, yet it is underutilized for diagnostic testing due to a lack of rapid and simple techniques for collecting abundant amounts of fluid. Here, we report a simple and minimally invasive technique for rapidly sampling larger quantities of ISF from human skin. A microneedle array is used to generate micropores in skin from which ISF is extracted using a vacuum-assisted skin patch. Using this technique, an average of 20.8 μL of dermal ISF is collected in 25 min, which is an ∼6-fold improvement over existing sampling methods. Proteomic analysis of collected ISF reveals that it has nearly identical protein composition as blood, and >600 medically relevant biomarkers are identified. Toward this end, we demonstrate the detection of SARS-CoV-2 neutralizing antibodies in ISF collected from COVID-19 vaccinees using two commercial immunoassays, showcasing the utility of this technique for diagnostic testing.

Microcrystal electron diffraction (MicroED) is an emerging structural technique in which submicron crystals are used to generate diffraction data for structural studies. Structures allow for the study of molecular-level architecture and drive hypotheses about modes of action, mechanisms, dynamics, and interactions with other molecules. Combining cryoelectron microscopy (cryo-EM) instrumentation with crystallographic techniques, MicroED has led to three-dimensional structural models of small molecules, peptides, and proteins and has generated tremendous interest due to its ability to use vanishingly small crystals. In this perspective, we describe the current state of the field for MicroED methodologies, including making and detecting crystals of the appropriate size for the technique, as well as ways to best handle and characterize these crystals. Our perspective provides insight into ways to unlock the full range of potential for MicroED to access previously intractable samples and describes areas of future development.

Recreating tissue environments with precise control over mechanical, biochemical, and cellular organization is essential for next-generation tissue models for drug discovery, development studies, and the replication of disease environments. However, controlling these properties at cell-scale lengths remains challenging. Here, we report the development of printing approaches that leverage polyethylene glycol diacrylate (PEGDA) hydrogels containing photocaged oligonucleotides to spatially program material characteristics with non-destructive, non-ultraviolet light. We further integrate this system with a perfusion chamber to allow us to alter the composition of PEGDA hydrogels while retaining common light-activatable photocaged DNAs. We demonstrate that the hydrogels can capture DNA functionalized materials, including cells coated with complementary oligonucleotides with spatial control using biocompatible wavelengths. Overall, these materials open pathways to orthogonal capture of any DNA functionalized materials while not changing the sequences of the DNA.

Cotton ovule cultures are a promising platform for exploring biofabrication of fibers with tailored properties. When the ovules' growth medium is supplemented with chemically synthesized cellulose precursors, it results in their integration into the developing fibers, thereby tailoring their end properties. Here, we report the feeding of synthetic glucosyl phosphate derivative, 6-deoxy-6-fluoro-glucose-1-phosphate (6F-Glc-1P) to cotton ovules growing , demonstrating the metabolic incorporation of 6F-Glc into the fibers with enhanced mechanical properties and moisture-retention capacity while emphasizing the role of molecular hierarchical architecture in defining functional characteristics and mechanical properties. This incorporation strategy bypasses the early steps of conventional metabolic pathways while broadening the range of functionalities that can be employed to customize fiber end properties. Our approach combines materials science, chemistry, and plant sciences to illustrate the innovation required to find alternative solutions for sustainable production of functional cotton fibers with enhanced and emergent properties.

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Nature has already suggested bioinspired functions. Beyond them, adaptive and trainable functions could be the inspiration for novel responsive soft matter beyond the state-of-the-art classic static bioinspired, stimulus-responsive, and shape-memory materials. Here, we describe magnetic assembly/disassembly of electrically conducting soft ferromagnetic nickel colloidal particles into surface topographical pillars for bistable electrical trainable memories. They allow magnetic sensing with adaptable and rescalable sensitivity ranges, enabled by bistable memories and kinetic concepts inspired by biological sensory adaptations. Based on the soft ferromagnetism of the nanogranular composition and the resulting rough particle surfaces prepared via a solvothermal synthesis, triggerable structural memory is achieved by the magnetic field-driven particle assembly and disassembly, promoted by interparticle jamming. Electrical conversion from current to frequency for electrical spikes facilitates rescalable and trainable frequency-based sensitivity on magnetic fields. This work suggests an avenue for designing trainable and adaptable life-inspired materials, for example, for soft robotics and interactive autonomous devices.

Understanding how different networks relate to each other is key for understanding complex systems. We introduce an intuitive yet powerful framework to disentangle different ways in which networks can be (dis)similar and complementary to each other. We decompose the shortest paths between nodes as uniquely contributed by one source network, or redundantly by either, or synergistically by both together. Our approach considers the networks' full topology, providing insights at multiple levels of resolution: from global statistics to individual paths. Our framework is widely applicable across scientific domains, from public transport to brain networks. In humans and 124 other species, we demonstrate the prevalence of unique contributions by long-range white-matter fibers in structural brain networks. Across species, efficient communication also relies on significantly greater synergy between long-range and short-range fibers than expected by chance. Our framework could find applications for designing network systems or evaluating existing ones.

Transcription factors (TFs) regulate gene expression by binding to specific DNA sequences and gating access to genes. Even when the binding of TFs and their cofactors to DNA is reversible, indicating a reversible control of gene expression, there is little knowledge about the molecular effect DNA has on TFs. Using single-molecule multiparameter fluorescence spectroscopy, molecular dynamics simulations, and biochemical assays, we find that the monomeric form of the forkhead (FKH) domain of the human FoxP1 behaves as a disordered protein and increases its folded population when it dimerizes. Notably, DNA binding promotes a disordered FKH dimer bound to DNA, negatively controlling the stability of the dimeric FoxP1:DNA complex. The DNA-mediated reversible regulation on FKH dimers suggests that FoxP1-dependent gene suppression is unstable, and it must require the presence of other dimerization domains or cofactors to revert the negative impact exerted by the DNA.

Hypervirulent is known for its increased extracellular polysaccharide production. Biofilm matrices of hypervirulent have increased polysaccharide abundance and are uniquely susceptible to disruption by peptide bactenecin 7 (bac7 (1-35)). Here, using confocal microscopy, we show that polysaccharides within the biofilm matrix collapse following bac7 (1-35) treatment. This collapse led to the release of cells from the biofilm, which were then killed by the peptide. Characterization of truncated peptide analogs revealed that their interactions with polysaccharide were responsible for the biofilm matrix changes that accompany bac7 (1-35) treatment. Ultraviolet photodissociation mass spectrometry with the parental peptide or a truncated analog bac7 (10-35) reveal the important regions for bac7 (1-35) complexing with polysaccharides. Finally, we tested bac7 (1-35) using a murine skin abscess model and observed a significant decrease in the bacterial burden. These findings unveil the potential of bac7 (1-35) polysaccharide interactions to collapse biofilms.

Peptide-based biopolymers have gained increasing attention due to their versatile applications. A naphthalene dipeptide (2NapFF) can form chirality-dependent tubular micelles, leading to supramolecular gels. The precise molecular arrangement within these micelles and the mechanism governing gelation have remained enigmatic. We determined, at near-atomic resolution, cryoelectron microscopy structures of the 2NapFF micelles LL-tube and LD-tube, generated by the stereoisomers (l,l)-2NapFF and (l,d)-2NapFF, respectively. The structures reveal that the fundamental packing of dipeptides is driven by the systematic π-π stacking of aromatic rings and that same-charge repulsion between the carbonyl groups is responsible for the stiffness of both tubes. The structural analysis elucidates how a single residue's altered chirality gives rise to markedly distinct tubular structures and sheds light on the mechanisms underlying the pH-dependent gelation of LL- and LD-tubes. The understanding of dipeptide packing and gelation mechanisms provides insights for the rational design of 2NapFF derivatives, enabling the modulation of micellar dimensions.

Pyridoxal 5'-phosphate (PLP), the biologically active form of vitamin B, is an essential cofactor in many biosynthetic pathways. The emergence of PLP-dependent enzymes as drug targets and biocatalysts, such as tryptophan synthase (TS), has underlined the demand to understand PLP-dependent catalysis and reaction specificity. The ability of neutron diffraction to resolve the positions of hydrogen atoms makes it an ideal technique to understand how the electrostatic environment and selective protonation of PLP regulates PLP-dependent activities. Facilitated by microgravity crystallization of TS with the Toledo Crystallization Box, we report the 2.1 Å joint X-ray/neutron (XN) structure of TS with PLP in the internal aldimine form. Positions of hydrogens were directly determined in both the α- and β-active sites, including PLP cofactor. The joint XN structure thus provides insight into the selective protonation of the internal aldimine and the electrostatic environment of TS necessary to understand the overall catalytic mechanism.

Lipid peroxidation is the driver of ferroptotic cell death. However, nonconjugated and conjugated polyunsaturated fatty acids potentiate ferroptosis differently, while some isoprenoid-derived lipids inhibit ferroptosis despite being highly oxidizable. In this perspective, we propose that different oxidation mechanisms and products contribute to the discrepancies in the lipids' potency in modulating ferroptosis. We first discuss the relative reactivities of various lipids toward two rate-determining free radical propagating mechanisms, hydrogen atom transfer (HAT) and peroxyl radical addition (PRA), and the resulting differential product profiles. We then discuss the role and regulation of lipid peroxidation in ferroptosis and the potential contributions of different oxidation products, such as truncated lipids and lipid electrophiles, from HAT and PRA mechanisms to the execution of ferroptosis. Lastly, we offer our perspective on the remaining questions to fully understand the process from lipid peroxidation to ferroptosis.

COVID-19 has led to over 6.8 million deaths worldwide and continues to affect millions of people, primarily in low-income countries and communities with low vaccination coverage. Low-cost and rapid response technologies that enable accurate, frequent testing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are crucial for outbreak prevention and infectious disease control. Here we produce and characterize cellulose fibers naturally generated by the bacterium as an alternative biodegradable substrate for manufacturing an eco-friendly diagnostic test for COVID-19. Using this green technology, we describe a novel and label-free potentiometric diagnostic test that can detect SARS-CoV-2 within 10 min and costs US$3.50 per unit. The test has bacterial cellulose (BC) as its substrate and a carbon-based electrode modified with graphene oxide and the human angiotensin-converting enzyme-2 (ACE2) as its receptor. Our device accurately and precisely detects emerging SARS-CoV-2 variants and demonstrates exceptional sensitivity, specificity, and accuracy for tested clinical nasopharyngeal/oropharyngeal (NP/OP) samples.

Antimicrobial peptides (AMPs) derived from natural toxins and venoms offer a promising alternative source of antibiotics. Here, through structure-function-guided design, we convert two natural AMPs derived from the venom of the solitary eumenine wasp into α-helical AMPs with reduced toxicity that kill Gram-negative bacteria and in a preclinical mouse model. To identify the sequence determinants conferring antimicrobial activity, an alanine scan screen and strategic single lysine substitutions are made to the amino acid sequence of these natural peptides. These efforts yield a total of 34 synthetic derivatives, including alanine substituted and lysine-substituted sequences with stabilized α-helical structures and increased net positive charge. The resulting lead synthetic peptides kill the Gram-negative pathogens and (PAO1 and PA14) by rapidly permeabilizing both their outer and cytoplasmic membranes, exhibit anti-infective efficacy in a mouse model by reducing bacterial loads by up to three orders of magnitude, and do not readily select for bacterial resistance.